Somatostatin (SRIF), a tetradecapeptide discovered by Brazeau et al., has been shown to have potent inhibitory effects on various secretory processes in tissues such as pituitary, pancreas and gastrointestinal tract. SRIF also acts as a neuromodulator in the central nervous system. These biological effects of SRIF, all inhibitory in nature, are elicited through a series of G protein coupled receptors, of which five different subtypes have been characterized (SSTR-1 to SSTR-5). These five subtypes have similar affinities for the endogenous SRIF ligands but have differing distribution in various tissues. SRIF binds to each of the five distinct receptor (SSTR) subtypes with relatively high affinity.
SRIF produces a variety of effects, including modulation of hormone release, e.g., growth hormone, glucagon, insulin, amylin, and neurotransmitter release. Some of these effects have been associated with its binding to a specific SRIF receptor. For example, the inhibition of growth hormone has been attributed to the somatostatin type-2 receptor (“SSTR-2”) (Raynor, et al., Molecular Pharmacol. 43:838 (1993); Lloyd, et al., Am. J. Physiol. 268:G102 (1995)), while the inhibition of insulin has been attributed to the somatostatin type-5 receptor (“SSTR-5”) (Coy, et al. 197:366–371 (1993)). Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly with GH secreting adenomas (acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas.
As is well known to those skilled in the art, SRIF and analogs thereof are useful in the treatment of a great variety of diseases and/or conditions. An exemplary but by no means exhaustive list of such diseases and/or conditions would include: Cushings Syndrome (see Clark, R. V. et al, Clin. Res. 38, p. 943A, 1990); gonadotropinoma (see Ambrosi B., et al., Acta Endocr. (Copenh.) 122, 569–576, 1990); hyperparathyroidism (see Miller, D., et al., Canad. Med. Ass. J., Vol. 145, pp. 227–228, 1991); Paget's disease (see, Palmieri, G. M. A., et al., J. of Bone and Mineral Research, 7, (Suppl. 1), p. S240 (Abs. 591), 1992); VIPoma (see Koberstein, B., et al., Gastroenterology, 28, 295–301, 1990 and Christensen, C., Acta Chir. Scand. 155, 541–543, 1989); nesidioblastosis and hyperinsulinism (see Laron, Z., Israel J. Med. Sci., 26, No. 1, 1–2, 1990, Wilson, D. C., Irish J. Med. Sci., 158, No. 1, 31–32, 1989 and Micic, D., et al., Digestion, 16, Suppl. 1.70. Abs. 193, 1990); gastrinoma (see Bauer, F. E., et al., Europ. J. Pharmacol., 183, 55 1990); Zollinger-Ellison Syndrome (see Mozell, E., et al., Surg. Gynec. Obstet., 170, 476–484, 1990); hypersecretory diarrhea related to AIDS and other conditions (due to AIDS, see Cello, J. P., et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A163 1990; due to elevated gastrin-releasing peptide, see Alhindawi, R., et al., Can. J. Surg., 33, 139–142, 1990; secondary to intestinal graft vs. host disease, see Bianco J. A., et al., Transplantation, 49, 1194–1195, 1990; diarrhea associated with chemotherapy, see Petrelli, N., et al., Proc. Amer. Soc. Clin. Oncol., Vol. 10, P 138, Abstr. No. 417 1991); irritable bowel syndrome (see O'Donnell, L. J. D., et al., Aliment. Pharmacol. Therap., Vol. 4., 177–181, 1990); pancreatitis (see Tulassay, Z., et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A238, 1990); Crohn's Disease (see Fedorak, R. N., et al., Can. J. Gastroenterology, 3, No. 2, 53–57, 1989); systemic sclerosis (see Soudah, H., et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A129, 1990); thyroid cancer (see Modigliani, E., et al., Ann., Endocr. (Paris), 50, 483–488, 1989); psoriasis (see Camisa, C., et al., Cleveland Clinic J. Med., 57 No. 1, 71–76, 1990); hypotension (see Hoeldtke, R. D., et al., Arch. Phys. Med. Rehabil., 69, 895–898, 1988 and Kooner, J. S., et al., Brit. J. Clin. Pharmacol., 28, 735P–736P, 1989); panic attacks (see Abelson, J. L., et al., Clin. Psychopharmacol., 10, 128–132, 1990); sclerodoma (see Soudah, H., et al., Clin. Res., Vol. 39, p. 303A, 1991); small bowel obstruction (see Nott, D. M., et al., Brit. J. Surg., Vol. 77, p. A691, 1990); gastroesophageal reflux (see Branch, M. S., et al., Gastroenterology, Vol. 100, No. 5, Part 2 Suppl., p. A425, 1991); duodenogastric reflux (see Hasler, W., et al., Gastroenterology, Vol. 100, No. 5, Part 2, Suppl., p. A448, 1991); Graves' Disease (see Chang, T. C., et al., Brit. Med. J., 304, p. 158, 1992); polycystic ovary disease (see Prelevic, G. M., et al., Metabolism Clinical and Experimental, 41, Suppl. 2, pp 76–79, 1992); upper gastrointestinal bleeding (see Jenkins, S. A., et al., Gut., 33, pp. 404–407, 1992 and Arrigoni, A., et al., American Journal of Gastroenterology, 87, p. 1311, (abs. 275), 1992); pancreatic pseudocysts and ascites (see Hartley, J. E., et al., J. Roy. Soc. Med., 85, pp. 107–108, 1992); leukemia (see Santini, et al., 78, (Suppl. 1), p. 429A (Abs. 1708), 1991); meningioma (see Koper, J. W., et al., J. Clin. Endocr. Metab., 74, pp. 543–547, 1992); and cancer cachexia (see Bartlett, D. L., et al., Surg. Forum., 42, pp. 14–16, 1991).
The variable sensitivity of acromegalic patients to the current clinically available SRIF agonists, octreotide and lanreotide, has already been underlined. (Ann Intern Med. 117:711–718 (1992); 3J Clin Endocrinol Metab 71:391–397 (1990)). An improved patient response has been reported using the long-lasting depot formulations of either octreotide or lanreotide (Flogstad A K, et al. 1997, J Clin Endocrinol Metab. 82:23–28; Caron P, et al., 1997, J Clin Endocrinol Metab. 82:18–22.). In these reports 70–80% of the acromegalic patients were considered to be controlled with these long-lasting SRIF agonists formulations. Such data were, in fact, biased due to preselection of patients already known to be responders through previous sc administration of octreotide. When such preselection is eliminated, the percentage of patients who achieve mean GH levels less than 2.5 μg/L with slow release lanreotide has been demonstrated in recent studies to be 50–60% (al-Maskari M, et al., 1996, Clin Endocrinol (Oxf). 45:415–421.). Thus, about 40–50% of acromegalic patients remain partially or poorly controlled under the current SRIF agonist treatments.
In acromegaly, a quantitative loss of SRIF receptors explains the very poor or absent GH suppression in response to acute administration of octreotide or SRIF in 3 of 17 cases (Ikuyama S, et al, 1985 J Clin Endocrinol Metab. 61:666–67;. Reubi J C, Landolt A M, 1989, J Clin Endocrinol Metab. 68:844–850). Such a loss of SRIF receptors is seldom encountered and cannot fully explain the partial GH-suppressive effects of octreotide and lanreotide in vivo. In a subsequent study of 37 GH-secreting tumors, the density of SRIF receptors was poorly correlated to the GH-suppressive effects of octreotide in vivo (Bertherat J, et al. 1993, J Clin Endocrinol Metab 77:1577–1583.). Another hypothesis that could explain the partial GH-suppressive effects of octreotide or lanreotide in certain acromegalic patients comes from the identification of 5 SSTR subtypes (Patel Y C, Srikant C B, 1994, Endocrinology. 135:2814–2817.). In human tumors of various origins, specific patterns of SSTR subtype expression have been described (Eden P A, Taylor J E. 1993, Life Sci. 53:85–90; Schaer J C, et al., 1997, Int J Cancer. 70:530–537.). Among the GH-secreting adenomas, a consistent pattern of SSTR2 and SSTR5 mRNA expression has been identified (Greenman Y, Melmed S. 1994, J Clin Endocrinol Metab. 78:398–403; Greenman Y, Melmed S. 1994, J Clin Endocrinol Metab. 79:724–729; Miller G M, et al., 1995, J Clin Endocrinol Metab. 4:1386–1392; Murabe H, et al. 1996, J Neuroendocrinol. 8:605–610; Nielsen S, et al. 1998, J Clin Endocrinol Metab. 83:2997–3000; Panetta R, Patel Y C. 1995, Life Sci. 56:333–342; Reubi J C, et al., 1994, Cancer Res. 54:3455–3459). Previous studies have shown an inhibition of GH release using SSTR2-preferential agonists. However, an SSTR5-preferential agonist has also been shown to induce a significant inhibition of GH release in 7 of 15 GH-secreting tumors (Jaquet P, et al. 2000, J Clin Endocrinol Metab. 85:781–792) and 6 of 7 GH-secreting tumors (Shimon I, et al., 1997, J Clin Invest. 100:2386–2392; Shimon I, et al. 1997, J Clin Invest. 4:789–798.).
These data implicate the SSTR5 subtype in the inhibition of GH release in certain tumors. This hypothesis is confirmed in our study using the bispecific SSTR2- and SSTR5-preferential compound of formula (I). Indeed, when the tumors were only responsive to SSTR2 preferential analogs, this compound was unable to produce any additional effect on inhibition of GH release compared with octreotide. However, in the tumors equally responsive to both SSTR2 and SSTR5 agonists, the compound of formula (I) was significantly more potent than octreotide in the suppression of GH and PRL secretion. The comparison between dose-response inhibition of GH release with the compound of formula (I) and SRIF-14 showed that this compound more closely mimicked the effects of native SRIF by acting via both SSTR2 and SSTR5 subtypes.
From our data, two classes of tumors emerged among the GH-secreting adenomas. The first was a series of tumors characterized by high sensitivity to SRIF-14 and SSTR2-preferential agonists. These tumors presented the highest level of SSTR2 mRNA expression and had the highest GH-suppressive effect with octreotide. In the second class of tumors, the level of SSTR2 mRNA was low, and octreotide produced only partial inhibition of GH release. SRIF-14 was nevertheless able to suppress GH release, with a maximal suppressive effect similar to that of the first class of tumors, but at a 10-fold higher concentration. The presence of high levels of SSTR5 mRNA was associated with a potent suppressive effect of Compound B on GH release, more efficacious than that of the SSTR2 analogs. In these tumors, the bispecific SSTR2 and SSTR5 compound of formula (I) induced a suppression of GH release identical to that achieved by native SRIF. Thus in tumors deficient in the SSTR2 subtype presenting with a high SSTR5/SSTR2 ratio there may be a rescue through the SSTR5 subtype that mediates the suppression of GH release.
Other indications associated with activation of the SRIF receptor subtypes are inhibition of insulin and/or glucagon and more particularly diabetes mellitus, angiopathy, retinopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding.
Additionally, the following references disclose the use of certain somatostatin analogs for the indications noted: U.S. Pat. No. 4,853,371—inhibiting the secretion of growth hormone, insulin, glucagon and pancreatic exocrine secretion; U.S. Pat. No. 5,147,856—restenosis; U.S. Pat. No. 5,411,943—hepatoma; U.S. Pat. No. 5,073,541—lung cancer; U.S. Pat. No. 5,504,069—inhibiting the accelerated growth of a solid tumor; U.S. Pat. No. 5,688,418—prolonging survival of pancreatic cells; U.S. patent application Ser. No. 08/089,410 filed Jul. 9, 1993—melanoma; U.S. patent application Ser. No. 08/854,941 filed May 13, 1997—decreasing body weight; U.S. patent application Ser. No. 08/854,943 filed May 13, 1997—insulin resistance and Syndrome X; U.S. patent application Ser. No. 08/855,311 filed May 13, 1997—hyperlipidemia; U.S. patent application Ser. No. 08/440,061 filed May 12, 1995—hyperamylinemia; U.S. patent application Ser. No. 08/852,221 filed May 7, 1997—hyperprolactinemia and prolactinomas; International Patent Application No. PCT/US97/14154—fibrosis.
It is preferred to have an analog which is selective for the specific SRIF receptor subtype or subtypes responsible for the desired biological response, thus, reducing interaction with other receptor subtypes which could lead to undesirable side effects. Further, because of the short half-life of native SRIF, various SRIF analogs have been developed, e.g., for the treatment of acromegaly, (Raynor, et al., Molecular Pharmacol. 43:838 (1993)).